Translational reprogramming as a driver of antimony-drug resistance in Leishmania

• Published in: Nature communications 2023-05, Vol.14 (1), p.2605-2605, Article 2605
• Main Authors: Gutierrez Guarnizo, Sneider Alexander, Tikhonova, Elena B., Karamyshev, Andrey L., Muskus, Carlos E., Karamysheva, Zemfira N.
• Format: Article
• Language: English
• Subjects: 13; 38; 45; 45/77; 45/88; 45/90; 45/91; 631/154/155; 631/326/417/1716; 631/337/574; Adaptation; Antimony; Antimony - pharmacology; Antiprotozoal Agents - pharmacology; Drug resistance; Drug Resistance - genetics; Energy metabolism; Gene expression; Gene regulation; Humanities and Social Sciences; Humans; Leishmania; Leishmania - genetics; Leishmaniasis; Molecular modelling; multidisciplinary; Parasite resistance; Phenotypes; Post-transcription; Preempting; Protein turnover; Science; Science (multidisciplinary); Translation; Vector-borne diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38221-1

Leishmania is a unicellular protozoan that has a limited transcriptional control and mostly uses post-transcriptional regulation of gene expression, although the molecular mechanisms of the process are still poorly understood. Treatments of leishmaniasis, pathologies associated with Leishmania infections, are limited due to drug resistance. Here, we report dramatic differences in mRNA translation in antimony drug-resistant and sensitive strains at the full translatome level. The major differences (2431 differentially translated transcripts) were demonstrated in the absence of the drug pressure supporting that complex preemptive adaptations are needed to efficiently compensate for the loss of biological fitness once they are exposed to the antimony. In contrast, drug-resistant parasites exposed to antimony activated a highly selective translation of only 156 transcripts. This selective mRNA translation is associated with surface protein rearrangement, optimized energy metabolism, amastins upregulation, and improved antioxidant response. We propose a novel model that establishes translational control as a major driver of antimony-resistant phenotypes in Leishmania . Leishmania is a unicellular protozoan that has limited transcriptional control. Here, the authors show that translational control is a major mechanism of antimony drug resistance in Leishmania . They observe a dramatic translatome reprogramming during development of resistance to the drug and report translational control as a major driver of antimony-resistant phenotypes.